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Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer

a technology of catalytic hydrogen transfer and which is applied in the field of reductive amination of 6keto normorphinans to form 6alphaamino epimers, can solve the problems of high reactive reducing agents, no 6-alpha-amino epimers provide stereoselective synthesis in good yield,

Active Publication Date: 2013-06-25
SPECGX LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although several methods for forming 6-amino morphinans from 6-keto morphinans have been reported in the literature, none provides the stereoselective synthesis of 6-alpha-amino epimers in good yield.
Furthermore, the existing methods require the use of highly reactive reducing agents and / or hydrogen gas.

Method used

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  • Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer
  • Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer
  • Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer

Examples

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Effect test

example 1

Reductive Amination of (−)-Noroxymorphone with Benzylamine

[0115]The following reaction scheme depicts the preparation of 6-alpha-amino derivatives of (−)-noroxymorphone:

[0116]

[0117]Reaction 1. Into a round bottom flask was added noroxymorphone (2.50 g, 0.009 moles), benzylamine (1.86 g, 0.017 moles, 1.83 mL), triethylamine (4.40 g, 0.044 moles, 6.06 mL), and acetonitrile (10 mL). To this solution was added >96% formic acid (5.01 g, 0.109 moles, 4.10 mL). The reaction temperature exothermed to 50° C. The reaction was stirred for 30 minutes until the temperature reached 25° C. Then, dichloro(p-cymene)Ru(II) dimer (27 mg) was added and the reaction was warmed to 60° C. for 18 h. LC indicated the noroxymorphone was consumed and two products were present, the N-formyl and the N—H compound. The reaction mixture was cooled to room temperature, and then evaporated to an oil. The residue was dissolved in acetonitrile (5 mL) and 29% NH3 / H2O was added dropwise until the pH of the mixture was 9...

example 2

Reductive Amination of (+)-Noroxymorphone with Benzylamine

[0119]A 6-alpha amino derivative of (+)-noroxymorphone was prepared according to the following reaction scheme:

[0120]

[0121]Reaction 1. Into a round bottom flask was charged (+)-noroxymorphone (0.50 g, 1.74 mmoles), acetonitrile (20.0 mL), and then benzylamine (0.37 g, 3.45 mmoles). This mixture was stirred at room temperature for 5 minutes, then triethylamine (0.88 g, 8.7 mmoles, 1.21 mL) was added. Next, >96% formic acid (1.0 g, 21.72 mmoles, 0.82 mL) was added dropwise. The temperature exothermed to 45° C. After the addition of formic acid was complete, dichloro(p-cymene) Ru(II) dimer (5 mg, 0.008 mmole) was added. The reaction mixture was stirred at 60° C. for 48 h. Then, an additional amount of >96% formic acid (0.61 g, 13.25 mmol, 0.5 mL) was added. After stirring for an additional 24 h at 60° C., the reaction was determined to by complete by HPLC. The reaction mixture was evaporated under reduced pressure to a thick oil...

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Abstract

The present invention provides processes for the stereoselective synthesis of 6-alpha-amino morphinans. In particular, the invention provides processes for the reductive amination of 6-keto normorphinans by catalytic transfer hydrogenation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 186,047 filed Jun. 11, 2009, which is incorporated herein in its entirety.FIELD OF THE INVENTION[0002]The present invention generally relates to the reductive amination of 6-keto normorphinans to form 6-alpha-amino epimers. In particular, the invention relates to the reductive amination of 6-keto normorphinans by catalytic hydrogen transfer to form N-formylated 6-alpha-amino epimers.BACKGROUND OF THE INVENTION[0003]Morphinans, including N-alkylated morphinans and normorphinans, are important pharmaceuticals, typically used as analgesics or drug / alcohol cessation agents. Substituted morphinans, such as 6-amino derivatives, may be useful therapeutically because they have higher efficacy, greater potency, and / or may function as prodrugs. Although several methods for forming 6-amino morphinans from 6-keto morphinans have been reported in the literature, none provides t...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D221/28
CPCC07D489/08C07D489/00
Inventor GROTE, CHRISTOPHER W.CANTRELL, GARY L.MCCLURG, JOSEPH P.THOMASSON, CATHERINE E.MOSER, FRANK W.
Owner SPECGX LLC
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